Nuclear RNR-α antagonizes cell proliferation by directly inhibiting ZRANB3

Nature Chemical Biology
Yuan FuYimon Aye

Abstract

Since the origins of DNA-based life, the enzyme ribonucleotide reductase (RNR) has spurred proliferation because of its rate-limiting role in de novo deoxynucleoside-triphosphate (dNTP) biosynthesis. Paradoxically, the large subunit, RNR-α, of this obligatory two-component complex in mammals plays a context-specific antiproliferative role. There is little explanation for this dichotomy. Here, we show that RNR-α has a previously unrecognized DNA-replication inhibition function, leading to growth retardation. This underappreciated biological activity functions in the nucleus, where RNR-α interacts with ZRANB3. This process suppresses ZRANB3's function in unstressed cells, which we show to promote DNA synthesis. This nonreductase function of RNR-α is promoted by RNR-α hexamerization-induced by a natural and synthetic nucleotide of dA/ClF/CLA/FLU-which elicits rapid RNR-α nuclear import. The newly discovered nuclear signaling axis is a primary defense against elevated or imbalanced dNTP pools that can exert mutagenic effects irrespective of the cell cycle.

References

Mar 1, 1992·Experimental Cell Research·V BianchiP Reichard
Oct 1, 1996·Journal of Structural Biology·R MarabiniJ M Carazo
Dec 16, 1997·Proceedings of the National Academy of Sciences of the United States of America·H FanJ A Wright
Aug 12, 1999·Mammalian Genome : Official Journal of the International Mammalian Genome Society·D M PitterleG Bepler
Feb 19, 2002·Chemical Reviews·JoAnne Stubbe, Wilfred A. van Der Donk
Apr 11, 2003·Oncogene·Ashish GautamGerold Bepler
Jun 7, 2003·Advances in Enzyme Regulation·Barry S Cooperman, Ossama B Kashlan
May 5, 2004·Proceedings of the National Academy of Sciences of the United States of America·Andrei SeluanovVera Gorbunova
May 15, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Gerold BeplerLary Robinson
Oct 13, 2004·Journal of Structural Biology·C O S SorzanoA Pascual-Montano
Apr 6, 2005·Journal of Molecular Biology·Sjors H W ScheresJose-Maria Carazo
Jun 8, 2006·Annual Review of Biochemistry·Pär Nordlund, Peter Reichard
Jul 25, 2006·The Journal of Biological Chemistry·Reza RofougaranAnders Hofer
Feb 23, 2007·The New England Journal of Medicine·Zhong ZhengGerold Bepler
Oct 29, 2008·Oncogene·B EwaldW Plunkett
Nov 11, 2008·Proceedings of the National Academy of Sciences of the United States of America·Giovanna PontarinVera Bianchi
Sep 9, 2009·The Journal of Cell Biology·Karin M GilljamMarit Otterlei
Feb 22, 2011·Nature Structural & Molecular Biology·James Wesley FairmanChris Godfrey Dealwis
Jun 2, 2011·Proceedings of the National Academy of Sciences of the United States of America·Yimon Aye, Joanne Stubbe
Nov 5, 2011·Critical Reviews in Biochemistry and Molecular Biology·Anders HoferBritt-Marie Sjöberg
Sep 27, 2014·Chembiochem : a European Journal of Chemical Biology·Yuan FuYimon Aye
Feb 2, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Hongyan QiJimin Shao
Aug 25, 2015·Nature Reviews. Cancer·Christopher K Mathews
Mar 6, 2016·The Biochemical Journal·Ning TsaoZee-Fen Chang

❮ Previous
Next ❯

Citations

Dec 28, 2018·Chembiochem : a European Journal of Chemical Biology·Marcus J C LongYimon Aye
Jun 23, 2020·Annual Review of Biochemistry·Brandon L GreeneJoAnne Stubbe
Apr 6, 2019·Frontiers in Chemistry·Marcus J C LongYimon Aye
Jul 14, 2019·The Journal of Biological Chemistry·Phong TranAndrei Chabes
Nov 12, 2020·Chembiochem : a European Journal of Chemical Biology·Marcus J C Long
Dec 15, 2019·Cell Chemical Biology·Marcus J C LongYimon Aye
Nov 18, 2019·Current Opinion in Chemical Biology·Marcus J C LongYimon Aye
Jan 28, 2022·Proceedings of the National Academy of Sciences of the United States of America·Yi ZhaoYimon Aye

❮ Previous
Next ❯

Methods Mentioned

BETA
xenografts
two-hybrid
Y2H
co-immunoprecipitation
nuclear
co-IP
nuclear translocation
cross-linking assay
transmission electron microscopy
Protein Assay

Software Mentioned

Image
EMAN
Xmipp
FlowJo
BLAST
Rotastat

Related Concepts

Related Feeds